A Glycyrrhizin Derivative with a More Potent Inhibitory Activity against High-Mobility Group Box 1 Efficiently Discovered by Chemical Synthesis Inspired by the Bioconversion Products of an Endophytic Fungus Isolated from Licorice

Glycyrrhizin (GL) from licorice alleviates intracerebral
hemorrhage
(ICH) injuries by interacting with high-mobility group box (HMGB)
1, an inflammatory factor. We found that GL is bioconverted by endophyte
coexisting with licorice and succeeded in isolating two derivatives.
The aim of this study was to identify the compound with more potent
HMGB1 inhibitory activity inspired by these GL derivatives. We took
advantage of a ketone introduced by an endophyte at the C-3 position
and attempted methyl esterification at the C-30 position because it
was suggested that the water or lipid solubility of the molecule plays
an important role. Among three derivatives synthesized, the product
that is both ketonized and esterified showed more potent HMGB1 inhibitory
activity than GL in macrophages and significantly improved adverse
events occurred in ICH in vivo. These results suggest that modification
of the hydrophilicity of GL, particularly at the C-3 and C-30 positions,
enhances the HMGB1 inhibitory activity.